New Animal Drugs; Cephalosporin Drugs; Extralabel Animal Drug Use; Order of Prohibition

Federal Register, Volume 77 Issue 4 (Friday, January 6, 2012)

Federal Register Volume 77, Number 4 (Friday, January 6, 2012)

Rules and Regulations

Pages 735-745

From the Federal Register Online via the Government Printing Office www.gpo.gov

FR Doc No: 2012-35

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 530

Docket No. FDA-2008-N-0326

New Animal Drugs; Cephalosporin Drugs; Extralabel Animal Drug Use; Order of Prohibition

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency) is issuing an order prohibiting certain extralabel uses of cephalosporin antimicrobial drugs in certain food-producing animals. We are issuing this order based on evidence that certain extralabel uses of these drugs in these animals will likely cause an adverse event in humans and, therefore, present a risk to the public health.

DATES: This rule becomes effective April 5, 2012. Submit either electronic or written comments on this document by March 6, 2012.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2008-

N-0326, by any of the following methods:

Electronic Submissions

Submit electronic comments in the following way:

Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions for submitting comments.

Written Submissions

Submit written submissions in the following ways:

Fax: (301) 827-6870.

Mail/Hand delivery/Courier (For paper, disk, or CD-ROM submissions): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

Instructions: All submissions received must include the Agency name and Docket No. FDA-2008-N-0326 for this rulemaking. All comments received may be posted without change to http://www.regulations.gov, including any personal information provided. For additional information on submitting comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this document.

Docket: For access to the docket to read background documents or comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the ``Search'' box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Eric Nelson, Center for Veterinary Medicine (HFV-230), Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855, (240) 276-9201, email: eric.nelson@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

1. Background

   1. History

      In the Federal Register of July 3, 2008 (73 FR 38110), FDA published an order prohibiting the extralabel use of cephalosporin antimicrobial drugs in food-producing animals, with a 60-day comment period and a 90-day effective date for the final order. The order, which was to take effect as a final rule on October 1, 2008, would have resulted in a change to part 530 (21 CFR part 530) in Sec. 530.41 to list cephalosporins as prohibited from extralabel use in food-producing animals as provided for in Sec. 530.25(f).

      Page 736

      In response to publication of this order, the Agency received requests for a 60-day extension of the comment period. The requests conveyed concern that the original 60-day comment period would not allow the requesters sufficient time to examine the available evidence, consider the impact of the order, and provide constructive comment.

      FDA considered the requests and, in the Federal Register of August 18, 2008 (73 FR 48127), extended the comment period for the order for 60 days, until November 1, 2008. Accordingly, FDA also delayed the effective date of the final rule 60 days, until November 30, 2008.

      The Agency received many substantive comments on the July 3, 2008, order of prohibition. Therefore, to allow more time to fully consider the comments, FDA decided to revoke the order so that it would not take effect November 30, 2008. Accordingly, in the Federal Register of November 26, 2008 (73 FR 71923), FDA withdrew the final rule and indicated that if, after considering the comments and other relevant information the Agency decided to issue another order of prohibition addressing this matter, FDA would follow the procedures in Sec. 530.25 that provide for a public comment period prior to implementing the new order.

   2. Comments on the July 3, 2008, Order of Prohibition

      The Agency received comments from approximately 170 organizations and individuals on the July 3, 2008, order of prohibition. Comments were received from a trade organization representing new animal drug manufacturers, several trade organizations representing food animal producers, several professional associations representing veterinarians, a consumer protection organization, several new animal drug manufacturers, and many individuals including food animal veterinarians, farmers, and ranchers. Only two of the commenters supported the July 3, 2008, order of prohibition as written. All others felt that the prohibition should be revised in some manner before enactment or that it was unnecessary and should not be enacted in any form. These comments can be summarized into two general categories:

      (1) The scope of the order was too broad in that it unnecessarily prohibited certain extralabel uses that do not significantly contribute to the problem of cephalosporin resistance. Many of these commenters were concerned about the unintended negative consequences on animal health that would result from such action; and

      (2) FDA failed to meet the legal standard for issuing a prohibition order. Some of these comments alleged that FDA appeared to have applied the ``precautionary principle'' rather than basing its decision on sound scientific evidence.

      Although FDA does not agree with comments alleging that the Agency did not meet the legal standard for issuing an order of prohibition, the Agency does agree with comments that the scope of the original order of prohibition could have been more targeted. After considering the comments and information submitted in response to the July 2008 order of prohibition, FDA has re-examined the basis for the original order. Based on this re-examination, FDA has determined that there is sufficient basis for prohibiting certain extralabel uses of cephalosporin drugs in food-producing major animal species. Specifically, as explained in detail later in this document, FDA is prohibiting the extralabel use of cephalosporin antimicrobial drugs (not including cephapirin) in cattle, swine, chickens, and turkeys: (1) For disease prevention purposes; (2) at unapproved doses, frequencies, durations, or routes of administration; and (3) if the drug is not approved for that species and production class.

      Thus, with the exception of extralabel uses of cephapirin, the final effect of this order will be to prohibit many extralabel uses of cephalosporin drugs in food-producing major animal species (cattle, swine, chickens, and turkeys) including:

      (1) Use for disease prevention purposes;

      (2) Use at unapproved dose levels, frequencies, durations, or routes of administration (e.g., Biobullets in cattle and injection or dipping of poultry eggs); and

      (3) Use of products not approved in the major food species (e.g., use of human or companion animal cephalosporin drugs).

      The extralabel uses that are not prohibited by this order include:

      (1) Use of approved cephapirin products in food-producing animals;

      (2) Use to treat or control an extralabel disease indication as long as such use adheres to a labeled dosage regimen (i.e., dose, route, frequency, and duration of administration) approved for that species and production class; and

      (3) Use in food-producing minor species.

      The Agency is prohibiting these extralabel uses in food-producing major species because we believe such uses in these animals will likely cause an adverse event in humans and, therefore, present a risk to the public health. FDA may further restrict extralabel use of cephalosporin antimicrobial drugs in animals in the future if it has evidence that demonstrates that such use has caused or likely will cause an adverse event.

2. Basis for Prohibiting the Extralabel Use of Cephalosporins With Certain Exceptions

   1. AMDUCA and Cephalosporins

      The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) (Public Law 103-396) was signed into law October 22, 1994. It amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act) to permit licensed veterinarians to prescribe extralabel uses of approved human and animal drugs in animals. In the Federal Register of November 7, 1996 (61 FR 57732), FDA published the implementing regulations (codified at part 530) for AMDUCA that include, among other things, a definition for the term ``extralabel use'' as well as provisions for prohibiting extralabel uses.

      Section 530.3 states that extralabel use means actual use or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling. This includes, but is not limited to:

      (1) Use in species not listed in the labeling;

      (2) Use for indications (disease or other conditions) not listed in the labeling;

      (3) Use at dose levels, frequencies, or routes of administration other than those stated in the labeling; and

      (4) Deviation from the labeled withdrawal time based on these different uses.

      The sections in FDA's implementing regulations governing the prohibition of extralabel use of drugs in animals include Sec. Sec. 530.21, 530.25, and 530.30. These sections describe the basis for issuing an order prohibiting an extralabel drug use in animals and the procedure to be followed in issuing such an order. FDA may issue a prohibition order if it finds that extralabel use of a drug in animals presents a risk to the public health. Under Sec. 530.3(e), this means that FDA has evidence demonstrating that the use of the drug has caused, or likely will cause, an adverse event. Furthermore, as discussed in section III.B of this document, the regulations permit a prohibition order to be either a general ban on the extralabel use of the drug or

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      class of drugs, or a ban limited to one or more of the uses described in the definition of extralabel use cited previously.

      Section 530.25 provides for a public comment period of not less than 60 days. It also provides that the order of prohibition become effective 90 days after the date of publication, unless FDA revokes or modifies the order, or extends the period of public comment. The list of drugs prohibited from extralabel use is found in Sec. 530.41.

      At this time, FDA is concerned that certain extralabel uses of cephalosporins in food-producing major species are likely to lead to the emergence and dissemination of cephalosporin-resistant strains of foodborne bacterial pathogens. If these drug-resistant bacterial strains infect humans, it is likely that cephalosporins will no longer be effective for treating disease in those people. The Agency is particularly concerned about the extralabel use of cephalosporin drugs that are not approved for use in food-producing major species because very little is known about their microbiological or toxicological effects when used in food-producing animals. Therefore, FDA is issuing an order prohibiting, with limited exceptions, the extralabel use of cephalosporins in food-producing major species because, as discussed in this document, the Agency has determined that such extralabel use likely will cause an adverse event and, therefore, presents a risk to the public health.

   2. Importance of Cephalosporins in Veterinary and Human Medicine

      Cephalosporins are members of the beta-lactam (beta-lactam) class of antimicrobials. Members of the cephalosporin class have a beta-

      lactam ring fused to a sulfur-containing ring-expanded system (Ref. 1). These antimicrobials work by targeting synthesis of the bacterial cell wall, resulting in increased permeability and eventual hydrolysis of the cell.

      Introduced into clinical use in 1964, cephalosporins are widely used antimicrobial agents in human medicine. Beta-lactams make up 40 percent of total prescriptions in the outpatient setting, and cephalosporins contribute 14 percent of the total outpatient antibiotic prescriptions. This use accounts for over 50 million prescriptions per year (Ref. 2). In the inpatient setting, cephalosporins are most commonly used to treat pneumonia. Older cephalosporins are widely used as therapy for skin and soft tissue infections caused by Staphylococcus aureus and Streptococcus pyogenes, as well as treatment of upper respiratory tract infections, intra-abdominal infections, pelvic inflammatory disease, and diabetic foot infections. Approved indications for newer cephalosporins include the treatment of lower respiratory tract infections, acute bacterial otitis media, skin and skin structure infections, urinary tract infections (complicated and uncomplicated), uncomplicated gonorrhea, pneumonia (moderate to severe), empiric therapy for febrile neutropenic patients, complicated intra-abdominal infections, pelvic inflammatory disease, septicemia, bone and joint infections, meningitis, and surgical prophylaxis. Indicated pathogens include, but are not limited to, Acinetobacter calcoaceticus, Bacteroides fragilis, Enterobacter agglomerans, Escherichia coli, Haemophilus influenzae (including beta-lactamase producing strains), Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes (Ref. 3). Newer cephalosporins (for example, third generation cephalosporins such as ceftriaxone) are used in the hospital setting to treat seriously ill patients with life-threatening disease, many of which are due to organisms that reside in the gastrointestinal tract. These newer cephalosporins are the antibiotics of choice in the treatment of serious Salmonella and Shigella infections, particularly in children where fluoroquinolones may be avoided due to potential for toxicity (Ref. 4).

      Two cephalosporin drugs are currently approved for use in food-

      producing animal species: Ceftiofur and cephapirin. Injectable ceftiofur products are approved for the treatment and control of certain diseases, including: (1) The treatment of respiratory disease in cattle, swine, sheep, and goats; (2) the treatment of acute bovine interdigital necrobacillosis (foot rot) and acute bovine metritis; (3) the control of bovine respiratory disease; and (4) the control of early mortality associated with E. coli infections in day-old chicks and poults. In addition, ceftiofur is approved as an intramammary infusion for the treatment of clinical mastitis in lactating dairy cattle associated with coagulase-negative staphylococci, Streptococcus dysgalactiae, and E. coli. Cephapirin is only approved as an intramammary infusion for the treatment of lactating cows having bovine mastitis caused by susceptible strains of Streptococcus agalactiae and Staphylococcus aureus.

   3. Mechanism of Cephalosporin Resistance

      In general, there are three major mechanisms by which bacteria become resistant to antimicrobial agents: (1) Alteration of the antimicrobial target, (2) efflux of the antimicrobial or changes in permeability of the bacterial cell, and (3) inactivation of the antimicrobial agent itself. Gram-negative bacterial resistance to cephalosporins occurs mainly through inactivation of the cephalosporin by beta-lactamases. These enzymes can be both innate and acquired (Ref. 5).

      Among bacteria of human health concern, the two most important classes of beta-lactamase enzymes are the AmpC cephalosporinases and the extended-spectrum beta-lactamases (ESBL). CMY-2 (a type of AmpC) enzymes are found on the chromosome of most Enterobacteriaceae, and are also currently found on promiscuous plasmids in Salmonella, E. coli, and other members of the Enterobacteriaceae. These enzymes provide resistance to first, second, and third generation cephalosporins. CMY-2 is currently the predominant beta-lactamase associated with Salmonella collected from animals and humans in the United States displaying resistance to ceftiofur and decreased susceptibility or resistance to ceftriaxone (Refs. 6-8), both third generation cephalosporins.

      ``Fourth generation'' cephalosporins are active in vitro against bacteria producing AmpC type beta-lactamases, but there is some disagreement as to the clinical significance of that activity. Recently, three E. coli producing variant CMY-2 beta-lactamases were isolated from patients in Pennsylvania. Two of the three patients from whom these isolates were obtained had undergone treatment with cefepime, a fourth generation cephalosporin, within the 2 months preceding isolation of the organisms. These isolates were shown to have reduced susceptibility to fourth generation cephalosporins, suggesting that CMY-2 has the potential to evolve to provide resistance to fourth generation cephalosporins when exposed to selective pressure (Ref. 9).

      ESBLs present in bacteria of human health concern include members of the TEM, SHV, and CTX-M families. These enzymes are plasmid-mediated and have the potential to provide resistance to all cephalosporins. Different ESBLs hydrolyze different cephalosporins at different efficiencies and rates, thus leading to varying patterns of in vitro susceptibility. In 2010, the CLSI revised

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      the cephalosporin resistance breakpoints to more accurately reflect in vivo susceptibility. Prior to this time, a particular ESBL strain that might not raise the minimum inhibitory concentration (MIC) for a given cephalosporin to a level above the breakpoint for resistance would commonly prove to be resistant in vivo (Ref. 5). Therefore, there were specific guidelines for screening bacterial isolates for the presence of ESBLs when MICs fell in the susceptible range. Any bacterial isolate which produced either an AmpC enzyme or an ESBL was reported to clinicians as resistant to all cephalosporins even though susceptibility testing may have shown in vitro susceptibility to some of the cephalosporins (Ref. 10).

      In a review of the CTX-M family of ESBLs, Livermore, et al. (Ref. 11) noted that until the late 1990s, European surveys found the TEM and SHV families of ESBLs almost exclusively. CTX-M enzymes were recorded rarely, although large outbreaks caused by Salmonella serovar Typhimurium with CTX-M-4 and CTX-M-5 were reported in Latvia, Russia, and Belarus in the mid-1990s. However, CTX-M enzymes are now the predominant ESBLs in many European countries, and E. coli has joined Klebsiella pneumoniae as a major host. CTX-M enzymes are supplanting TEM and SHV in East Asia as well as in Europe. Only in the United States do TEM and SHV still predominate, although CTX-M enzymes are now rising in prevalence (Refs. 12-19). Once mobilized, CTX-M enzymes can be hosted by many different genetic elements, but are most often found on large multi-drug resistance plasmids. Therefore, FDA is concerned that if CTM-X becomes prevalent in the United States, as has occurred in other countries, cephalosporin resistance may escalate.

      Serious infections caused by cephalosporin-resistant bacteria may be empirically treated with ineffective antibacterial regimens, significantly increasing the likelihood of death. Urinary tract infections caused by community-acquired cephalosporin-resistant E. coli may be associated with bloodstream infections, and these infections may also be resistant to most or all antibiotics commonly used to treat such infections. Empirical treatment of such infections is often with a fluoroquinolone, amoxicillin-clavulanate, or a cephalosporin; however, these E. coli are likely to be resistant to all of these agents, making treatment of these infections more difficult (Ref. 11).

   4. Cephalosporin-Resistant Zoonotic Foodborne Bacteria

      In regard to antimicrobial drug use in animals, the Agency considers the most significant risk to the public health associated with antimicrobial resistance to be human exposure to food containing antimicrobial-resistant bacteria resulting from the exposure of food-

      producing animals to antimicrobials, including cephalosporins. Resistance to certain cephalosporins is of particular public health concern in light of the evidence of cross-resistance among drugs in the cephalosporin class. Importantly, resistance to ceftiofur compromises the efficacy of ceftriaxone, a first-line therapy for treating salmonellosis in humans. A recent review of beta-lactam resistance in bacteria of animal origin states that an emerging issue of concern is the increase in reports of CMY-2 and CTX-M beta-lactamases (Ref. 6), which confer cephalosporin resistance and are transmissible between enteric bacteria. Acquired resistance to beta-lactams in animal and human isolates has been observed in surveillance programs such as the U.S. National Antimicrobial Resistance Monitoring System (NARMS) and the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS).

      Because food-producing animals are a known source of resistant Salmonella infections in humans (Ref. 20), the NARMS program has monitored ceftiofur resistance among Salmonella isolates from food-

      producing animals at slaughter since 1997. In 1997, no Salmonella isolates from cattle or swine were resistant to ceftiofur, while ceftiofur resistance among isolates from chickens and turkeys was 0.5 percent and 3.7 percent, respectively. By 2009, the prevalence of ceftiofur resistance among Salmonella slaughter isolates increased to 14.5 percent for cattle, 4.2 percent for swine, 12.7 percent for chickens, and 12.4 percent for turkeys (Ref. 21).

      Among food animal Salmonella isolates in NARMS, ceftiofur resistance has been identified in more than 20 different serotypes, and it has increased substantially in several serotypes commonly found in humans (Ref. 22). Ceftiofur resistance among all Salmonella Typhimurium isolates from chickens was 0.0 percent in 1997 and 33.3 percent in 2009. Among all Salmonella Typhimurium isolates from cattle, ceftiofur resistance was 3.0 percent in 1998 and 27.8 percent in 2009. Ceftiofur resistance rose from 12.5 percent in 1998 to 58.8 percent in 2009 among Salmonella Newport isolates from cattle. There was no ceftiofur resistance among Salmonella Heidelberg isolates from poultry in 1997, but resistance rose to 17.6 percent in chicken isolates and 33.3 percent in turkey isolates in 2009 (Refs. 22, 23).

      The NARMS program has also monitored ceftiofur resistance among Salmonella isolates from humans since 1996. Ceftiofur resistance among non-Typhi Salmonella isolates from humans rose from 0.2 percent in 1996 to 3.4 percent in 2009. Resistance to ceftiofur also rose in several Salmonella serotypes commonly isolated from humans. In 1996, ceftiofur resistance among Salmonella isolates from humans was 0.0 percent, 0.0 percent, and 1.4 percent for serotypes Typhimurium, Newport, and Heidelberg, respectively. In 2009, ceftiofur resistance among isolates from these serotypes was 6.5 percent, 6.4 percent, and 20.9 percent, respectively (Refs. 23, 24).

      The CIPARS program revealed an increase in Quebec of resistance to cephalosporins among Salmonella Heidelberg isolates from humans reaching a level of 36 percent of isolates in 2004. This increase was accompanied temporally by an increase in ceftiofur resistance in Salmonella Heidelberg isolates from retail chicken, which rose to 62 percent in 2004. Hatcheries in Quebec voluntarily stopped the use of ceftiofur in eggs and day-old chicks in February 2005. This action was followed temporally by a dramatic decline in the prevalence of ceftiofur resistance in Salmonella Heidelberg isolates from humans and retail chicken in Quebec, which by 2008 had declined to 12 percent and 18 percent, respectively. These trends in Salmonella Heidelberg were accompanied by similar trends in ceftiofur resistance in E. coli isolates from retail chicken (Ref. 25).

      Ceftiofur is not used in human medicine in the United States, but after the 2010 CLSI change in the cephalosporin breakpoint, resistance to this agent largely coincides with resistance to ceftriaxone, a third generation cephalosporin that is a critically important antimicrobial approved for use in humans (Ref. 23). As discussed earlier, this resistance trait conferred by the CMY-2 enzyme. CMY-2 provides resistance to first, second, and third generation cephalosporins. In addition to conferring ceftiofur and ceftriaxone resistance, CMY-2 also imparts resistance to several other beta-lactams, including ampicillin and amoxicillin/clavulanate (Ref. 26). The prevalence and spread of CMY-2 is reflected in the surveillance data on ceftriaxone and ceftiofur susceptibility

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      (Ref. 27) and supports the finding that cephalosporin use in food-

      producing animals is likely contributing to an increase in cephalosporin-resistant human pathogens.

   5. Extralabel Uses of Greatest Concern

      1. Dairy Cattle

         The U.S. Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS) conducts both ante-mortem and post-mortem inspection of livestock and poultry presented for slaughter at each official establishment. As part of ante-mortem inspection, FSIS personnel inspect animals to determine whether they exhibit behaviors or conditions that are indicative of illegal chemical use. If such behaviors or symptoms are exhibited, the animals are tagged and further examined at post-mortem inspection. During post-mortem inspection, FSIS veterinarians examine carcasses and their organs to determine whether the animals they came from had pathological diseases or other conditions that could have warranted the use of drugs or other chemicals and whether there are any indications of illegal chemical use. In addition, FSIS conducts laboratory analysis of sample tissues that have been taken from carcasses that have pathologies or other conditions indicative of chemical use to determine whether they contain violative chemical residues. FSIS transmits to FDA information about the violative chemical residue found, including the name of the official establishment where the livestock or poultry was presented for slaughter.

         During the 1-year period ending June 25, 2009, FSIS reported 113 instances of violative ceftiofur residues in dairy cows and an additional 22 instances of violative ceftiofur residues in other food-

         producing animals, including beef cattle and veal calves. The FSIS reports include quantitative drug residue levels for each violation. In most instances, the violative residue levels of ceftiofur detected in dairy cows were significantly above the allowable tolerance of 0.4 ppm (kidney) in tested tissues and are summarized as follows:

         Up to 2x above the tolerance = 12 violations

         Between 2x and 5x above the tolerance = 17 violations

         Between 5x and 10x above the tolerance = 16 violations

         Between 10x and 20x above the tolerance = 30 violations

         Over 20x above the tolerance = 38 violations

         An examination of 25 recent inspections of farms responsible for violative ceftiofur residues identified a number of factors that resulted in the misuse of ceftiofur animal drug products. These factors include, but were not limited to, the following: (1) Poor or nonexistent animal treatment records for adequately monitoring treated animals; (2) inadequate animal identification systems for monitoring treated animals; (3) animal owners' lack of knowledge regarding withdrawal times associated with the animal drug product; (4) the animal drug product was administered by a route not included in the approved labeling; (5) the animal drug product was administered at a dose higher than stated in the approved labeling; and (6) the animal drug product was administered to a type of animal (e.g., veal calves) not listed in the approved labeling. Most of the violations involved culled dairy cows. More than half of the violations involved ceftiofur residue levels more than 10 times the established tolerance level.

         Based on investigations conducted by FDA, the majority of residue violations were the result of poor recordkeeping and other management practices. Among the provisions required for extralabel drug use in animals under 21 CFR part 530, the client (the owner of the animal or animals or other caretaker) must agree to follow the instructions of the veterinarian, the veterinarian must institute procedures to assure that the identity of the treated animal or animals is carefully maintained, and the veterinarian must take appropriate measures to assure that assigned timeframes for withdrawal are met and no illegal drug residues occur in any food-producing animal subjected to extralabel treatment.

         Adhering to the ELU requirements is particularly important for extralabel drug use in dairy cattle because treatment often occurs in sick adult dairy cows close to the time of potential slaughter and introduction into the food supply. Evidence of this practice is the fact that 67 percent of all tissue residue violations reported by FSIS at slaughter are attributed to adult dairy cattle. In comparison, antimicrobial drug treatment in swine and beef cattle more often occurs earlier in the life of the animal, typically at some transition point that is well before slaughter. This aspect of dairy husbandry is not only a concern regarding violative drug residues, it is also a concern in the context of antimicrobial resistance. Recent evidence suggests that administration of ceftiofur crystalline-free acid (CCFA) in cattle will cause a transient increase in the population of ceftiofur-

         resistant isolates in gut bacteria that lasts approximately two weeks before a return to more normal susceptibility patterns (Ref. 28). Because of this, the Agency is concerned that improper extralabel use of ceftiofur in culled dairy cows just prior to slaughter could result in increased levels of cephalosporin resistance in carcass bacteria.

         Ceftiofur use in dairy herds has been shown to increase herd prevalence of ceftriaxone resistant E. coli over that in herds without ceftiofur use. Herds reporting ceftiofur use were 25 times more likely to have cows from which ceftriaxone resistant E. coli were isolated than those that did not use ceftiofur (Ref. 29). In addition, a ceftiofur-resistant fecal E. coli isolate expressing CTX-M-type extended-spectrum beta-lactamase was recovered from a sick dairy calf that was treated in an extralabel manner for diarrhea with ceftiofur (Ref 17). Escherichia coli are considered good indicators of the selective pressure imposed by antimicrobial use in food-producing animals and, as such, may reflect what might occur in Salmonella spp. under the same conditions (Ref. 30). Salmonella Newport has been shown to be the predominant serotype among cases of clinical salmonellosis in dairy cattle, followed by S. Typhimurium, including the S. Typhimurium variant, 4,5,12:i:- (Refs. 31, 32). Over 68 percent of all isolates were resistant to five or more antimicrobials in these studies. In one study, 97 percent of S. Newport isolates were multi-drug resistant (MDR), exhibiting an MDR-AmpC phenotype (Ref. 31). The proportion of multi-drug resistance was significantly higher (p 152, http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/ucm126971.htm (accessed January 6, 2011), September 25, 2006.

      3. U.S. Food and Drug Administration, MAXIPIME (cefepime hydrochloride) for Injection, NDA 50-679/S-021, http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/050679s028lbl.pdf (accessed January 6, 2011).

      4. Biedenbach, D.J. et al. Analysis of Salmonella spp. with resistance to extended-spectrum cephalosporins and fluoroquinolones isolated in North America and Latin America: report from the SENTRY Antimicrobial Surveillance Program (1997-2004). Diagnostic Microbiology and Infectious Disease 54:13-21, 2006.

      5. Livermore, D.M. Beta-Lactamases in Laboratory and Clinical Resistance.

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         Clinical Microbiology Review 8:557-584, 1995.

      6. Li, X.Z. et al. beta-Lactam Resistance and beta-lactamases in Bacteria of Animal Origin. Veterinary Microbiology 121:197-214, 2007.

      7. Centers for Disease Control and Prevention (CDC), National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS): Human Isolates Final Report, 2008. Atlanta, Georgia: U.S. Department of Health and Human Services, CDC, 2010.

      8. Glenn, L.M. et al. Analysis of Antimicrobial Resistance Genes Detected in Multidrug-Resistant Salmonella enterica Serovar Typhimurium Isolated from Food Animals. Microbial Drug Resistance 17:407-418, 2011.

      9. Doi, Y. et al. Reduced Susceptibility to Cefepime among Escherichia coli Clinical Isolates Producing Novel Variants of CMY-2 beta-Lactamase. Antimicrobial Agents and Chemotherapy 53:3159-

         3161, 2009.

      10. Clinical and Laboratory Standards Institute, Performance Standards for Antimicrobial Susceptibility Testing: Sixteenth Informational Supplement, M100-S16, Wayne, PA, USA: CLSI, 2006.

      11. Livermore, D.M. et al. CTX-M: Changing the Face of ESBLs in Europe. J. Antimicrobial Chemotherapy 59:165-174, 2007.

      12. Lewis, J.S. et al. First Report of the Emergence of CTX-M-Type Extended-Spectrum szlig-Lactamases (ESBLs) as the Predominant ESBL Isolated in a U.S. Health Care System. Antimicrobial Agents and Chemotherapy 51:4015-4021, 2007.

      13. Castanheira, M. et al. Rapid Emergence of blaCTX-M Among Enterobacteriaceae in U.S. Medical Centers: Molecular Evaluation From the MYSTIC Program (2007). Microbial Drug Resistance 14:211-

          216, 2008.

      14. Sjoumllund-Karlsson, M. et al. Human Salmonella Infection Yielding CTX-M beta-Lactamase, United States. Emerging Infectious Diseases 14:1957-1959, 2008.

      15. McGettigan, SE. et al. Prevalence of CTX-M beta-Lactamases in Philadelphia, Pennsylvania. Journal of Clinical Microbiology 47:2970-2974, 2009.

      16. Sjoumllund-Karlsson, M. et al. Salmonella Isolates with Decreased Susceptibility to Extended-Spectrum Cephalosporins in the United States. Foodborne Pathogens and Disease 7:1503-1509, 2010.

      17. Wittum, T.E. et al. CTX-M-Type Extended-Spectrum szlig-

          Lactamases Present in Escherichia coli from the Feces of Cattle in Ohio, United States. Foodborne Pathogens and Disease 7:1575-1579, 2010.

      18. Naseer, U. and A. Sundsfjord. The CTX-M Conundrum: Dissemination of Plasmids and Escherichia coli Clones. Microbial Drug Resistance 17:83-97, 2011.

      19. Sjoumllund-Karlsson, M. et al. CTX-M-producing Non-Typhi Salmonella spp. Isolated from Humans, United States. Emerging Infectious Diseases 17:97-99, 2011.

      20. Moslashlbak, K. Spread of Resistant Bacteria and Resistance Genes from Animal to Humans--The Public Health Consequence. Journal of Veterinary Medicine B51:364-369, 2004.

      21. USDA, ``National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS): Animal Arm Annual Report, 2009,'' Athens, Georgia, U.S. Department of Agriculture, USDA, 2011.

      22. FDA, ``National Antimicrobial Resistance Monitoring System-

          Enteric Bacteria (NARMS): 2009 Executive Report,'' Rockville, MD, U.S. Department of Health and Human Services, Food and Drug Administration, 2011.

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      24. CDC, ``National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS): Human Isolates Final Report, 2009,'' Atlanta, Georgia, U.S. Department of Health and Human Services, CDC, 2011.

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          List of Subjects in 21 CFR Part 530

          Administrative practice and procedure, Advertising, Animal drugs, Labeling, Reporting and recordkeeping requirements.

          Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs and redelegated to the Director of the Center for Veterinary Medicine, 21 CFR part 530 is amended as follows:

          Page 745

          PART 530--EXTRALABEL DRUG USE IN ANIMALS

          0

      1. The authority citation for 21 CFR part 530 continues to read as follows:

         Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b, 371, 379e.

         0

      2. In Sec. 530.41, add paragraph (a)(13) to read as follows:

         Sec. 530.41 Drugs prohibited for extralabel use in animals.

         (a) * * *

         (13) Cephalosporins (not including cephapirin) in cattle, swine, chickens, or turkeys:

         (i) For disease prevention purposes;

         (ii) At unapproved doses, frequencies, durations, or routes of administration; or

         (iii) If the drug is not approved for that species and production class.

         * * * * *

         Dated: November 23, 2011.

         Bernadette Dunham,

         Director, Center for Veterinary Medicine.

         FR Doc. 2012-35 Filed 1-4-12; 11:15 am

         BILLING CODE 4160-01-P